Surgery is the only treatment option that offers a cure for PDAC. Surgery aims to completely resect the tumor and achieve a microscopically negative tumor margin (R0). R0 dissection is defined as clearance of > 1 mm i.e., the margin of healthy tissue around the removed tumor should be > 1 mm. The various surgical options include pancreaticoduodenectomy (Whipple’s procedure) and distal pancreatectomy. Pancreaticoduodenectomy with SMA first approach is the standard of care for adenocarcinoma localized to the head of the pancreas (HOP). The surgery should involve dissection of greater than 15 lymph nodes and skeletonization of SMA down to adventitia of anterior, left lateral and posterior borders[21,22]. A sampling of para-aortic lymph nodes with an examination of the frozen section is an additional option. For PDAC involving the body and tail of the pancreas, distal pancreatectomy along with splenectomy is the treatment option. This involves dissection of greater than 15 lymph nodes[23,24].

Minimally invasive techniques for pancreatic resection beginning with laparoscopic distal pancreatectomy have been attempted. They offer advantages in the form of reduced blood loss and decreased hospital stay. However, the rate of achieving positive resection margin, morbidity, and mortality of the procedure remains the same as that of an open procedure. The use of robotic techniques in Whipple’s procedure has shown reduced rates of post-procedure complications[25]. Traditionally pre-operative biliary drainage has been advised for patients who present with obstructive jaundice. Recent evidence, however, points towards a higher rate of perioperative complications among those undergoing pre-operative drainage vs those undergoing upfront surgery[26].

The risk of developing tumor recurrence among those patients who undergo curative resection for PC varies from 69%-75% at 2 years to 80%-90% at 5 years post-surgery[27]. Tumor recurrence occurs secondary to locoregional occurrence in a majority of cases. This led to the hypothesis that the use of adjuvant therapy may reduce locoregional tumor recurrence.

Post-operative complications may reduce a patients’ access to adjuvant CT and overall survival. Hence, it becomes imperative to screen patients who are at high risk of post-operative complications, like elderly patients, patients with poor performance status, or higher comorbidity profiles. Preoperative pancreatic resection score (PREPARE) and Surgical results analysis and search (SOAR) are validated and useful scoring systems for assessing the risk of developing complications post-operatively[28,29].

The gold standard treatment for resectable PC is surgery followed by adjuvant CT. The era of adjuvant CT gained prominence when the results of the European Group for Pancreatic Cancer (ESPAC-1) trial showed significant improved median survival and 5-year survival in patients who received adjuvant CT of fluorouracil and folinic acid vs those who underwent surgery alone (20.1 mo vs 15.5 mo, respectively; P = 0.009). This was followed by the CONKO-001 (Charité Onkologietrial) trial, using adjuvant gemcitabine, which showed a median disease-free survival of 13.4 mo and 5-year survival of 20.7% vs 10.4% vs 6.9 mo respectively in the surgery alone group. The efficacy of these two treatment regimens was compared in the ESPAC-3 trial. Results of this study showed no survival benefit of one treatment regimen over the other, however, the treatment-related adverse effects were higher in the fluorouracil and folinic acid group.

To further improve the therapeutic outcome with adjuvant CT, a concept of combination systemic therapy has evolved. Several agents have been studied in various trials (Table 1). Among those of note are the ESPAC-4, PRODIGE and APACT studies. The ESPAC-4 trial carried out a comparison of gemcitabine vs a combination of gemcitabine plus capecitabine, which showed favorable overall survival benefit while using combination therapy [hazard ratio (HR): 0.82, 95% confidence interval (CI): 0.68-0.98; P = 0.032]. However, no significant recurrence-free survival benefit was seen in 2 years of follow-up of these patients (HR: 0.86, 95%CI: 0.73-1.02; P = 0.082). The Partenariat de Recherche en Oncologie Digestive (PRODIGE 24-PA6) trial highlighted the successful use of FOLFIRINOX (oxaliplatin + irinotecan + leucovorin) vs gemcitabine in patients with good performance status (Eastern Cooperative Oncology Group, ECOG: 0-1). The median disease-free survival in patients with combination therapy was 21.6 mo vs 12.8 mo in the gemcitabine group. The latest in series is the Nab-paclitaxel and Gemcitabine vs Gemcitabine Alone as Adjuvant Therapy for Patients with Resected Pancreatic Cancer (APACT) study, which has shown encouraging results of using combination therapy of gemcitabine plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel). Median disease-free survival was not statistically significant in the two arms (19.4 mo in combination arm vs 18.8 mo in gemcitabine only arm). Overall survival favored the combination CT group (HR: 0.82, 95%CI: 0.68-0.996; P = 0.045)[27].

Another concept is the use of targeted agents (erlotinib or sorafenib) or immunotherapy (algenpantucel-L) in combination with gemcitabine. However, to date, none of these agents have shown any favorable survival outcome vs the use of gemcitabine alone[30-32].

Adjuvant CRT aims to prevent locoregional tumor recurrence. Amongst the first trials to assess the efficacy of CRT in PC was the EORTC trial, which showed no significant survival benefit amongst patients of PDAC who received CRT (40 Gy + continuous infusion of fluorouracil)[13]. This was followed by the ESPAC-1 trial, which employed the following three different adjuvant therapy designs: CRT, CT alone, and CRT followed by adjuvant CT. Patients undergoing adjuvant CT were found to have poor survival benefits after a median follow-up of 47 mo (HR: 1.28, 95%CI: 0.99-1.66; P = 0.05)[34]. The RTOG 9704 trial was carried out to assess the benefit of adding gemcitabine to postoperative radiation + fluorouracil vs adjuvant therapy with fluorouracil. The trial showed no survival benefit in either of the two treatment groups[38].

Although these trials failed to prove any survival benefit, they nevertheless provided useful information on the feasibility and tolerability of these treatment options. Analysis of the US National Cancer Database which included patients of pancreatic adenocarcinoma who underwent curative resection followed by adjuvant CT showed survival benefit (median overall survival with CT + radiation: 22.3 mo and adjuvant CT alone: 20.0 mo; P = 0.001)[14].

There are definite gaps in our knowledge regarding the optimal timing of initiating CT following surgery and follow-up of patients undergoing adjuvant therapy for curable PC. Delay in initiating as well as non-initiation of adjuvant treatment is not uncommon. Post-operative morbidity adversely impacts the initiation of adjuvant treatment. It has been estimated that approximately 20% of patients become ineligible for adjuvant CT. The ESPAC-3 trial aimed to analyze the outcome among those who were initiated on CT within 8 wk of surgery and those who were initiated on CT after 8 wk of surgery. There was no survival benefit in either of the two arms, while successful completion of six cycles of CT was found to be an independent predictor of survival[39]. Similar results have been put forward by analyzing multi-institutional retrospective data of patients who had undergone curative resection for PDAC. Thus, the evidence so far suggests that patients who receive adjuvant therapy more than 12 wk following surgery are still good candidates for adjuvant CT[40].

Therefore, in summary, the standard of care in resectable pancreatic adenocarcinoma is surgical resection followed by adjuvant CT. Single-agent (5-FU) is preferred for periampullary tumors of pancreatic origin. Patients with adenocarcinoma in the head, body, or tail of the pancreas may be treated with FOLFIRINOX (patients with good post-operative performance status, ECOG: 0-1) and combination therapy of gemcitabine+ capecitabine in those with poor performance status postoperatively (Figure 1).

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Figure 1 Management of resectable pancreatic adenocarcinoma. 5-FU: 5-Fluorouracil; ECOG: Eastern Cooperative Oncology Group.

Conceptually, the use of neoadjuvant therapy in resectable PC gained prominence when this approach was shown to have improved survival benefit in other gastrointestinal malignancies[41]. It offers the following theoretical advantages: reduction of circulating tumor cells and micrometastasis before surgery, and avoiding surgery in those who experience disease progression while on neoadjuvant therapy, thus, reducing surgical mortality and morbidity. Of particular interest is the ability of neoadjuvant treatment to achieve tumor downsizing or downstaging (lower T and N stages, reducing the rates of vascular, lymphatic, and perineural invasion, and the ability to achieve better R0 resection post-surgery). Moreover, individuals who receive neoadjuvant CT are more likely to be able to access the entire therapeutic sequence[42,43].

The preoperative or postoperative CT for resectable pancreatic adenocarcinoma (PACT-15) trial has shown the efficacy of neoadjuvant CT in patients with resectable PDAC[44]. One of the first published phase III trials assessing the role of neoadjuvant gemcitabine followed by gemcitabine and radiation before surgery is the PREOPANC trial. Although it has not shown statistically significant survival benefit in patients using neoadjuvant CT + CRT (overall survival of 16 mo for neoadjuvant therapy vs 14.3 mo for initial surgery), better R0 resection rates, locoregional disease-free survival, and lower rates of vascular and perineural invasion favor neoadjuvant CT[45]. Analyses of ‘US National Cancer Database data have shown a favorable survival using perioperative CT in patients with early PC as compared with upfront surgery. Another similar cohort study by Mokdad and colleagues[46] demonstrated statistically significant median overall survival in the neoadjuvant group vis a vis upfront surgery group (26 mo vs 23 mo respectively; P = 0.01). Many other phase III trials are being conducted to have a better understanding of this therapeutic aspect[27] (Table 2). Neoadjuvant treatment is well tolerated. The risk of postoperative pancreatic fistula formation (3%-11%), risk of postoperative infections (3%-7%) and mortality (0%-4%) compared to those who have undergone surgery alone[47].

Palliative treatment aims to allay patients’ symptoms and improve their quality of life. Pain management, symptomatic relief, and psychological support are the pillars of this strategy.

Gastric outlet obstruction (GOO), extrahepatic biliary obstruction (EHBO), and abdominal pain are the three most common disabling symptoms in APC which adversely affect an individual’s quality of life besides being a major source of ‘caregiver fatigue’. GOO, presenting as nausea, vomiting, dehydration, and weight loss, is seen in 10%-25% of all APC cases. Palliative surgery with open gastrojejunostomy (GJ) is the traditional approach to managing a malignant GOO. Placement of endoscopic duodenal stents and laparoscopic GJ has been tried, with varying degrees of success. Surgical procedures offer good functional outcomes at the cost of increased mortality[71]. EHBO can present with obstructive jaundice. Endoscopic retrograde cholangiopancreatography (ERCP)-guided biliary stent placement is the accepted gold standard approach for the management of malignant EHBO. Both plastic and self-expanding metal stents (SEMSs) have been used, with literature favoring the use of covered SEMSs. Failure of ERCP-guided biliary drainage may warrant drainage through the percutaneous route or an endoscopic ultrasonography-guided biliary drainage (EUS BD)[72]. Hepaticojejunostomy with a Roux-en-Y reconstruction and cholecystectomy is the favored palliative surgical procedure for palliation of EHBO secondary to PC. Laparoscopic biliary bypass and robot-assisted laparoscopic hepaticojejunostomy have been technically successful with satisfactory surgical outcomes[73,74]. Thus, patients with good performance status may benefit from a palliative surgical procedure while those with poor performance status warrant endoscopic biliary drainage.

Malignant infiltration of celiac or mesenteric nerve plexus in patients of APC may cause abdominal and back pain. This may adversely affect an individual’s quality of life. Multimodal drug therapy encompassing the use of non-steroidal anti-inflammatory drugs and or opioid analgesics in various combinations form the bedrock of pain management. Intraoperative celiac block using ethanol or a local anesthetic using either laparoscopic or open approach and EUS-guided neurolysis of celiac plexus, have all been tried[71] (Figure 4).

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Figure 4 Palliative management in metastatic pancreatic carcinoma. ERCP: Endoscopic retrograde cholangiopancreatography; EUS: Endoscopic ultrasound; EUS-BD: Endoscopic ultrasound guided biliary drainage; GJ: Gastrojejunostomy; HJ: Hepaticojejunostomy; PTBD: Percutaneous transhepatic biliary drainage; SEMS: Self-expanding metal stent.

The tumor microenvironment of PC is responsible for aggressiveness as well as chemoresistance. This makes the case for utilizing immunotherapy in the advanced and metastatic settings. However, the approval for ICI is currently for patients with mismatch repair-deficient cases[69]. The updated results of the Keynote-158, using pembrolizumab in patients with advanced PDAC revealed an overall response rate (ORR) of 18.2%, median progression-free survival of 2.1 mo, and median overall survival of 4.0 mo[75]. The results are not very encouraging despite this, due to fewer driver mutations, variable expression of PD-1/PD-L1 and neoantigen burden in the tumor tissue, and absence of DDR, which are hallmarks of this malignancy[76].

The highly actionable mutations detected in molecular profiling of the Know Your Tumor initiative were 27%, of which the common ones involved the KRAS, TP53, MLL3, CDKN2A, SMAD4, TGFBR2, ARID1A, and SF3B1 genes. These mutations, however, do not have any therapeutic modality to target[77,78]. Neurotrophic receptor tyrosine kinase (NTRK) gene fusions have been detected in about 6% of pancreatic adenocarcinomas. Larotrectinib and entrectinib are two newer agents receiving accelerated approval for use in metastatic tumors with NTRK gene biomarker with tissue agnostic indication[79,80]. Three single-arm trials, namely LOXO-TRK-14001, SCOUT and NAVIGATE, had a total of 55 patients with NTRK fusions and had an ORR of 55% with Larotrectinib[81]. The median progression-free survival was not achieved after a median duration of 9.9 mo. Similarly, in three other single-arm trials, including ALKA-372-001, STARTRK-1 and STARTRK-2, with 60 patients in total, the patients with NTRK fusion had an ORR of 100%[82].

Germline BRCA1/2 mutations and homologous recombination deficiency enable the utility of platinum agents as well as poly (adenosine diphosphate-ribose) polymerase (PARP) inhibition as a novel therapeutic modality. Olaparib, a PARP inhibitor was approved by the United States’ Food and Drug Administration in December 2019 for patients with advanced metastatic malignancy having germline BRCA1/2 mutation. The phase III POLO trial utilizing olaparib in PAC, progressing after platinum-based therapy revealed median progression-free survival of 7.4 mo vs 3.8 in the control arm (HR: 0.53, 95%CI: 0.35-0.82; P = 0.004). This did not translate into an overall survival benefit[83].

Macrophages residing in the tumor environment are labeled as tumor-associated macrophages. CD 51 is a marker of macrophages that promotes the stemness of PDAC cells by regulating the TGF-β1/smad2/3 pathway. As a result, CD 51- targeted therapy is evolving as a newer therapeutic modality. Similarly, CD 40 activation, which promotes anti-tumor T-cell responses has been targeted by using anti-CD 40 antibody, CP-870893 along with gemcitabine, providing initial results of response[84].

The ability of cancer vaccines to stimulate dendritic cell responses and activate the adaptive immune responses has been harnessed for many cancers, including PC. The expression of murine enzyme alpha-1,3-galactosyltransferase (alpha-GT) by genetic engineering on PC cell lines HAPa1 and HAPa2 lead to anti-alpha-Gal antibody responses in humans[85]. Algenpanteucel-L was used in a phase II study and phase III (IMPRESS Trial). When algenpanteucel-L was given after gemcitabine and 5-FU based CRT, 81%-86% 1-year disease-free survival and 96% 1-year overall survival were observed[86,87].

GVAX, a line of engineered pancreatic tumor cells secreting GM-CSF has been tested in phase I study along with cyclophosphamide (Cy) with early results of tolerability and survival. In a phase II study, GVAX/Cy was tested against a GVAX/Cy followed by CRS 207 (a live-attenuated Listeria strain that induces tumor-associated antigens) and resulted in better overall survival in the latter arm (6.1 mo vs 3.9 mo, P = 0.02)[88].

There have been numerous trials using targets like vascular endothelial growth factor (VEGF) and VEGF-receptor, RAS-RAF-MEK-ERK pathway, etc. but none have shown robust survival data[89,90]. The rapamycin-insensitive companion of mTOR (RICTOR) expression was found to have a survival benefit in resected PAC patients, with those having a lower expression doubling the survival as compared to the high expressers[91].